This invention is concerned with certain 1,4-dihydropyridines, their preparation, pharmaceutical compositions containing them and their use as therapeutic agents, particularly as anti-ischaemic and anti-hypertensive agents.
The compounds of the invention delay or prevent the cardiac contracture which is believed to be caused by an accumulation of intracellular calcium under ischaemic conditions. Calcium overload, during ischaemia, can have a number of additional adverse effects which would further compromise the ischaemic myocardium. These include less efficient use of oxygen for ATP production, activation of mitochondrial fatty acid oxidation, and possibly, promotion of cell necrosis. Thus, the compounds are useful in the treatment or prevention of cardiac conditions, such as angina pectoris, cardiac arrythmias, heart attacks and cardiac hypertrophy. The compounds also possess vasodilator activity and are thus useful as antihypertensives and for the treatment of coronary vasospasm.
The compounds of the invention are calcium channel antagonists which are characterized by the presence of certain nitrogen-containing heterocyclic substituents in carboxylic ester groups substituted on the 3 and, optionally, also on the 5 positions of the dihydropyridine ring.
The structure and presumed mode of action of the 1,4-dihydropyridine calcium antagonists have been reviewed recently in the literature, see Meyer, et al., Annual Reports in Medicinal Chemistry, 1983, Chapter 9 and Janis, et al., J. Med. Chem 26, 775 (1983). One of the earliest compounds discovered, and still a standard against which new compounds are measured, is nifedipine (U.S. Pat. No. 3,485,847 to Bossert), in which the 2 and 6 positions are substituted by methyl groups, the 4 position by 2-nitrophenyl and the 3 and 5 positions by carboxylic acid methyl ester groups. Similar compounds are disclosed in U.S. Pat. Nos. 3,455,945; 3,325,505; and 3,441,468 to Loew and U.S. Pat. Nos. 3,470,297 and 3,511,837 to Bossert, which introduced variations in the 4-substituent. U.S. Pat. Nos. 3,905,970 to Bossert, et al., and 3,985,758 to Marakami, et al., introduced certain mono- or dialkylamino-alkylene and nitrogen-containing heterocyclic alkylene groups into one or both of the 3,5 ester groups. U.S. Pat. Nos. 4,307,103 and 4,393,070 to Sato disclose 1,4-dihydropyridines in which the 2 position is not substituted by alkyl, but instead is substituted with cyano, formyl or certain other substituents and the ester group in the 3 position may contain various substituted alkyl groups including substituted alkyl aminoalkyl, heterocyclic aminoalkyl and aroylaminoalkyl including phthalimidoethyl. U.S. Pat. No. 4,448,964 to Muto, et al., discloses compounds in which the 3-position ester group contains certain substituted piperidinyl alkylene groups.
It is recognized that useful 1,4-dihydropyridines have a wide variety of structures; however, the need for superior activity and specificity remains, and the effect of any particular structural modification on the properties of the compound is generally unpredictable. This is particularly true of modifications in the esters at the 3 and 5 positions, and of modifications at the 2 and 5 positions.